Parkinson's Disease
Parkinson's disease occurs in approximately one in 200 people during their lifetime. The disease may include hand and finger tremor, general akinesia, inability to get up from a chair, slow gait, stooped posture, expressionless face, constipation, among other symptoms.
Parkinson's disease is caused by a marked reduction in the content of dopamine in the brain, especially in the caudate nucleus and the putamen, regions important in regulating the control of arms, legs and body motion.
Types of Anti-Parkinson Medications
There are many types of anti-Parkinson medications used in clinical practice. These medications include:
1. L-DOPA taken orally. The L-DOPA enters the brain regions that are low in dopamine, and the L-DOPA is metabolized in those regions to produce dopamine. High doses of several grams per day of L-DOPA may be needed. Other medications can be taken simultaneously to minimize the metabolism of L-DOPA by other body tissues, thus providing higher concentrations of circulating L-DOPA.
2. Dopamine D2 receptor agonists, which include bromocriptine, apomorphine, N-propylnorapomorphine, pramipexole, cabergoline, pergolide, and quinagolide.
3. Many other medications affecting adenosine or cholinergic neurotransmission are also being examined for the alleviation of Parkinson's disease.
Use of Antipsychotics in Parkinson's Disease
In treating various psychoses, including schizophrenia, effective doses of antipsychotic drugs occupy between 60% and 80% of the dopamine D2 receptors in the brain striata of patients, as measured by PET or SPET in the human striatum. Clozapine and quetiapine, however, have consistently been apparent exceptions. For example, in patients taking therapeutically effective antipsychotic doses of clozapine, this drug only occupies between 0% and 50% of brain dopamine D2 receptors, as measured by a variety of radioligands using either positron tomography or single photon tomography.
Although the apparently low occupancy of D2 by clozapine might suggest that D2 is not the major antipsychotic target for clozapine, the apparently low occupancy of D2 by clozapine and quetiapine is readily explained by the fact that these two antipsychotics rapidly dissociate from the dopamine D2 receptor. This also holds for remoxipride and amisulpride, two atypical drugs. For example, human cloned dopamine D2 receptors release [3H]clozapine, [3H]quetiapine, [3H]remoxipride and [3H]amisulpride at least one hundred times faster than they release [3H]haloperidol or [3H]chlorpromazine.
These in vitro data match those found clinically for clozapine, quetiapine and haloperidol in schizophrenia patients and volunteers. For example, it has been found by PET (using [11C]raclopride) that the human brain (striatum) occupancy of D2 by quetiapine and clozapine rapidly falls off within 24 hours, in contrast to that for haloperidol which maintains its D2 occupancy constant over 24 hours.
Thus, the rapid release of clozapine and quetiapine from dopamine D2 receptors and their replacement by endogenous dopamine would readily account for the low D2 receptor occupancy shown by these atypical antipsychotics. It is important to emphasize that the rapid release of clozapine and quetiapine is a molecular event which occurs quickly regardless of the clinical dose used. In other words, even though high doses of clozapine and quetiapine may be used in the patient, these drugs continue to go on and off the D2 receptor rapidly, allowing extensive and frequent access of endogenous dopamine to the receptor.
As outlined above, the “fast-off” theory of atypical antipsychotic action is that the atypicals have low affinities for the dopamine D2 receptor, and are loosely bound to, and rapidly released from, these receptors. A critical aspect of the theory is that the atypical antipsychotics bind more loosely to D2 than does dopamine itself, while the traditional, typical antipsychotics bind more tightly than dopamine.
The separation between typical and atypical antipsychotics is not sharp and precise, because antipsychotics with dissociation constants (K values) between 2 nM and 10 nM often reveal dose-dependent extrapyramidal signs. Thus, the demarcation between typical and atypical antipsychotics is not a sharp divide but rather a continuous one. Antipsychotics become increasingly more atypical as their binding to the D2 receptor becomes looser and they are released more quickly. Although many atypical antipsychotics have loose binding, with dissociation constants looser than 1.8 nM (nanomoles per liter), they can still elicit dose-dependent Parkinsonism. For example, olanzapine, with a dissociation constant of 5.1 nM, is known to be associated with a dose-dependent incidence of extrapyramidal signs in some patients and especially at higher doses. If the binding is extremely “loose,” as with clozapine, remoxipride, quetiapine, and melperone, essentially no EPS occurs (although exquisitely sensitive patients do exist who will exhibit EPS even with these drugs). Drugs that are too “loose” or have far too low an affinity for D2 receptors cease to exhibit any antipsychotic activity at all. Moreover, although the degree of occupancy of atypicals at D2 receptors has a direct influence on EPS, the potent anticholinergic action of olanzapine and clozapine provides an additional anti-EPS mechanism.
L-DOPA Psychosis
The “Fast-off-D2” theory, described above, predicts low doses of atypical antipsychotics to alleviate L-DOPA psychosis. The treatment of patients with psychosis in Parkinson's disease (as a consequence of L-DOPA treatment) is best done with a very loose binding atypical antipsychotic, such as clozapine or quetiapine, to allow for the low level of dopamine neurotransmission that is required for normal motor functioning to continue. Parkinson patients are dopamine-depleted so it is generally important to not block the low level of dopamine function that remains. The hypothesis is that atypical antipsychotic action (i.e., low EPS) occurs when endogenous dopamine is able to displace a loosely bound antipsychotic. This is in accord with the observation that low doses of atypical antipsychotics are useful for Parkinson patients with L-DOPA psychosis.
L-DOPA psychosis in a Parkinson's diseased patient is best treated with a dose of clozapine which is about 10% of the dose normally used for treating psychosis in schizophrenia. The “fast-off-D2” hypothesis readily and quantitatively predicts this. As presented above, the antipsychotic dose needed to occupy D2 receptors is proportional to K×[1+D/DHigh], where K is the dissociation constant of the antipsychotic, D is the concentration of dopamine in the synaptic space during the momentary nerve impulse (˜200 nM), and where DHigh is the dissociation constant of dopamine at the high-affinity state of D2 (1.75 nM). In Parkinson's disease, where 90% to 95% of the dopamine content is absent, the value for D would be 20 nM. Accordingly, the antipsychotic dose for L-DOPA psychosis will be lower than that for schizophrenia psychosis by a factor of {1+D/DHigh}normal/{1+D/DHigh}Parkinson or {1+200/1.75}/{1+20/1.75} or 10-fold (P. Seeman. Canad. J. Psychiat. 47: 27-38, 2002).
Thus, while a daily dose of 500 mg clozapine might be suitable for treating schizophrenia psychosis, a dose of 50 mg (or less) would be more than adequate to treat L-DOPA psychosis.
Haloperidol
Haloperidol is a first generation “typical” antipsychotic medication. Associated with this class of drugs are many side-effects. Using the customary daily doses of 5 to 20 mg of oral haloperidol per day on a long-term basis, the following are such side effects. Cardiovascular effects include: tachycardia, hypotension, and hypertension, QT prolongation and/or ventricular arrhythmias, ECG patterns indicating torsade de pointes, and sudden and unexpected death. Central nervous system effects include extrapyramidal signs (EPS) such as Parkinson-like signs, akathisia or dystonia (including opisthotonos and oculogyric crises), tardive dyskinesia and tardive dystonia. The following are other central nervous system effects associated with the use of standard antipsychotic doses of haloperidol: insomnia, restlessness, anxiety, euphoria, agitation, drowsiness, depression, lethargy, headache, confusion, vertigo, and grand mal seizures. Neuroleptic malignant syndrome (NMS), hyperpyrexia and heat stroke have been reported with haloperidol.
The following is a current list of indications for the use of haloperidol: acute psychosis, such as drug-induced psychosis (LSD, amphetamines, phencyclidine), acute mania, hyperactivity, aggression, agitation and confusion associated with cerebral sclerosis, adjunctive treatment of alcohol and opioid withdrawal, treatment of neurological disorders such as tics, Tourette syndrome, and chorea, treatment of severe nausea/emesis (postoperative, side-effects of radiation and cancer chemotherapy), adjunctive treatment of severe chronic pain, always together with analgesics, personality disorders such as borderline personality disorders and in the treatment of intractable hiccups.